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Abstract

Objective

To determine the prevalence of, and patient characteristics associated with, antiplatelet
therapy in a cohort of primary care patients with Type 1 or Type2 diabetes.

Methods

Subjects participating in a randomized trial of a decision support system were interviewed
at home and medication usage verified by a research assistant. Eligibility for antiplatelet
therapy was determined by American Diabetes Association criteria and clinical contraindications.
The association between antiplatelet use and patient characteristics was examined
using bivariate and multivariate logistic regression.

Results

The mean age of subjects was 64 years (range 31–93). The prevalence of antiplatelet
use was 54% overall; 45% for subjects without known CVD vs. 78% for those with CVD;
46% for women vs. 63% for men; and 45% for younger subjects (age< 65) vs. 62% for
senior citizens. After controlling for race/ethnicity, income, education, marital
status, insurance status and prescription coverage, the following were associated
with the use of antiplatelet therapy: presence of known CVD (OR 3.4 [2.2, 5.1]), male
sex (OR 2.0 [1.4, 2.8]), and age > = 65 (OR 1.9 [1.3, 2.7]). The prevalence of antiplatelet
therapy for younger women without CVD was 32.8% compared to a prevalence of 90.3%
for older men with CVD.

Conclusion

Despite clinical practice guidelines recommending antiplatelet therapy for patients
with diabetes, there are still many eligible patients not receiving this beneficial
therapy, particularly patients under 65, women, and patients without known CVD. Effective
methods to increase antiplatelet use should be considered at the national, community,
practice and provider level.

Introduction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in adults
with diabetes [1-4]. Antiplatelet therapy, with either aspirin or the newer platelet aggregation inhibitors,
has been shown to be safe and cost effective for reducing the risk of recurrent vascular
events [5-8]. Consensus guidelines recommend the use of antiplatelet therapy for both primary
and secondary prevention of CVD [9,10]. In 1997, the American Diabetes Association (ADA) recommended antiplatelet therapy
for adults with diabetes and co-existing CVD, and for adults with diabetes over 30
years of age, even in the absence of CVD [11]. Prior to the publication of the ADA recommendations for antiplatelet prophylaxis,
the national rate of aspirin use among patients with diabetes was estimated at 13%
for individuals without CVD and at 37% for those with CVD [12]. By 2001 this latter prevalence, as determined by telephone survey, had increased
to 48.7% [13]. Current estimates suggest that approximately 5% of adults cannot tolerate aspirin
therapy. For these individuals, an alternative antiplatelet agent may be used [14].

Despite increasing evidence to support its effectiveness among patients with diabetes,
antiplatelet therapy has been under-utilized [12,15,16], particularly in women [13]. While several observational studies have examined the prevalence of aspirin use
both before and after the publication of the 1997 ADA recommendations, none have included
the use of other antiplatelet agents and may therefore have underestimated the prevalence
of antiplatelet therapy. The goal of this study is to determine the prevalence of
antiplatelet therapy (aspirin and newer platelet aggregation inhibitors) for both
primary and secondary prevention of CVD in diabetes and to examine the patient characteristics
that are associated with failure to use this important therapy.

Methods

This study was part of a larger project, the Vermont Diabetes Information System (VDIS),
a cluster-randomized trial of a laboratory-based diabetes decision support system
in a region-wide sample of 7295 adults with diabetes from 55 community Primary Care
practices [17]. We did not distinguish between Type 1 and Type 2 diabetes because this distinction
is not clinically important when recommending antiplatelet therapy. A field survey
targeted at a sub-sample of subjects was designed to provide a better understanding
of the non-laboratory features of diabetes. Patients were selected at random from
the subjects in each practice participating in the VDIS trial and invited by phone
to participate in an in-home interview. Patient names were randomly sorted and patients
contacted by telephone until a sample of approximately 15% of the patients from each
practice agreed to an interview. We attempted to contact 4209 patients and reached
1576. Of these, 1006 agreed to be interviewed. Demographic information including age,
sex, race, ethnicity, education, income, marital status and history of cardiovascular
disease were obtained by questionnaire. A complete list of medications was obtained
by a research assistant by direct observation of all of the medication containers
and recording of the medication name, dose, frequency and route of administration.
The interviews occurred between July 2003 and March 2005. The University of Vermont
Institutional Review Board approved the study and all subjects gave written informed
consent to participate in the interview.

For the purposes of this cross-sectional study, a subset of interviewed subjects was
created using inclusion and exclusion criteria based on the current American Diabetes
Association (ADA) recommendations for the use of antiplatelet therapy [18]. The subset of subjects who were eligible for antiplatelet therapy consisted of all
subjects in the VDIS interview cohort 30 years or older, and those under 30 years
with a self-reported history of either coronary heart disease, stroke or transient
ischemic attack, or peripheral vascular disease. For the purposes of the study we
defined cardiovascular disease (CVD) as any of the above manifestations of vascular
disease. We excluded patients with specific contraindications to antiplatelet therapy:
peptic ulcer disease (144), severe liver disease (13), and those on current warfarin
therapy (75), for whom decisions about concomitant use of antiplatelet therapy and
anticoagulation would be individualized. No information was available about side effects
or previous discontinuation of therapy was available. Some subjects had more than
one exclusion; a total of 221 subjects were excluded for a final sample of 785 subjects.
Antiplatelet use was defined as daily use of aspirin (at least 75 mg/day); clopidogrel;
ticlodipine; or cilostazol; or a combination of aspirin and clopidogrel, ticlodipine,
or cilostazol daily. The specific indication for the anti-platelet agent in each subject
was not known.

We used logistic regression to test the bivariate association of anti-platelet use
with variables that were potentially important based on previous research and clinical
judgment, including age, sex, race/ethnicity, income, education, marital status, insurance
status and pharmacy benefits, years since diagnosis of diabetes, smoking, body mass
index, frequency of visits to primary care physician, specialist involvement in care
(endocrinologist visit in the last year, attendance at a diabetes education class
within the last year), and the various categories of CVD. Variables that demonstrated
an association in bivariate modeling at a significance level of p < 0.1 were further
examined with multivariate regression modeling in which insignificant (p > 0.05) variables
were eliminated in a backward stepwise fashion.

Results

The characteristics of the study population are presented in Table 1. The mean age was 64 years with half the population over age 65. Most graduated high
school and fewer than 3% were uninsured. Most subjects were overweight or obese (89%),
with 18% falling in the severely obese category (body mass index of 40 or greater).
Twenty-six percent of the population had cardiovascular disease, with myocardial infarction
being the most common manifestation in 16%.

The prevalence of antiplatelet use was 53.6% (47.3% aspirin alone, 2.5% newer platelet
aggregation inhibitor and 3.8% both) for all eligible subjects and 78.2% for subjects
with known CVD. The characteristics associated with antiplatelet medication use are
noted in Table 2. Male sex and older age are both associated with a two-fold increase in antiplatelet
use (p < 0.001). Cardiovascular disease was associated with a three-fold increase
in antiplatelet use, with MI showing a six-fold increase (p < 0.001). Other factors
that were associated with anti-platelet agent use were: an endocrinology visit in
the previous year (p = 0.004), and Medicare insurance coverage (p < 0.001).

Table 2. Bivariate Associations with Anti-Platelet Use in Adults with Diabetes

In multivariable analysis, three characteristics remained independently associated
with antiplatelet use while controlling for important covariates (see Table 3). Subjects with a history CVD were more likely to be on appropriate antiplatelet
therapy (OR 3.4 [CI 2.2, 5.1]), as were subjects 65 or older (OR 1.9 [CI 1.3, 2.7])
and men (OR 2.0 [CI 1.4, 2.8]), (p < 0.001 for each). Table 4 indicates the prevalence of antiplatelet use in each of these patient subgroups.
The lowest rates are among women under 65 without CVD (32.8%), and highest among older
men with known CVD (90.3%).

Table 3. Multivariate Model of Characteristics Associated with Anti-Platelet Use in Adults
with Diabetes*

Among the 206 subjects with known CVD we found similar associations with antiplatelet
use with age > 65 (OR 3.0 CI [1.4, 6.3]), and male sex (OR 3.3 [1.5, 7.1]).

Discussion

We found a prevalence of antiplatelet therapy use among adults with diabetes of 53.6%
(47.3% aspirin alone, 2.5% newer platelet aggregation inhibitor and 3.8% both), which
is similar to the recent nationally representative telephone survey estimate of aspirin
use of 48.7% by Persell [13]. Among patients with CVD we found a prevalence of antiplatelet therapy of 78.2%,
compared to 74.2% by Persell [13].

We found the highest rates among subjects with CAD. Following the CAPRIE trial in
1996, which showed a slight advantage in secondary prevention of cardiovascular events
for clopidogrel vs. aspirin, clopidogrel has been increasingly used both in addition
to aspirin and as its replacement [19,20]. The newer platelet aggregation inhibitors are also increasingly used for acute coronary
syndrome and after percutaneous coronary intervention [21]. The strong evidence for CAD indications is reflected in our findings that subjects
with coronary artery disease were the most likely to be receiving antiplatelet therapy.

Our motivation in exploring the factors associated with antiplatelet agent use was
to help identify subgroups that may be targeted for special efforts to increase antiplatelet
therapy. We found that women, patients younger than 65, and those without CVD were
less likely to be using antiplatelet therapy. On the other end of the spectrum, over
90% of men over 65 with CVD were taking antiplatelet therapy. This high level of use
among those at the highest risk supports the achievability of the consensus guidelines.
A recent meta-analysis including 287 studies and 135,000 patients at high vascular
risk showed that antiplatelet therapy reduced serious vascular events (non-fatal MI,
non-fatal stroke, vascular death) by 36 (SE 5) per 1000 patients treated for two years
[22]. Assuming that we can move from our overall prevalence of antiplatelet therapy of
54% to our best rate of 90%, we estimate that another 13 serious vascular events per
1000 could be averted over two years. If this is projected to the 18.2 million adults
with diabetes in the United States [23], we estimate that 238,000 serious vascular events could be averted.

Why are patients with diabetes not receiving antiplatelet therapy despite consensus
guidelines? First of all, prescribers may feel there is some ambiguity regarding the
role of aspirin in CVD primary prevention for patients with diabetes. For example,
while the Primary Prevention Project, which randomized over 4000 diabetic and non-diabetic
subjects with CVD risk factors to aspirin or no aspirin, was stopped early because
of the beneficial effects of aspirin, in the subgroup with diabetes the benefits were
smaller and not statistically significant. [24] This raises the question of potential differences in the role of antiplatelet therapy
in diabetes. Secondly, even if prescribers agree with the guideline, there are other
barriers to achieving perfect compliance. A qualitative study exploring reasons cited
by physicians for not prescribing aspirin included: difficulties in applying generic
guidelines to individuals, patient resistance to taking aspirin, prioritization of
other issues in a time constrained visit, and communication problems in reviewing
the medications of patients with stroke [25].

Why might women be less likely to be receiving antiplatelet therapy? Gender differences
have been well documented in the diagnosis and treatment of heart disease [26] In addition, the effects of aspirin may be different in men and women; a recent study
of primary prevention of CVD in almost 40,000 women over 45 years of age showed that,
while stroke risk was lowered, myocardial infarction and overall cardiovascular mortality
were not [27]. Physicians may be less enthusiastic about the evidence base supporting the use of
antiplatelet therapy in women. For patients under age 65, physicians (and patients
themselves) may not perceive the risks of CVD as high enough to warrant antiplatelet
therapy.

We observed an association between the use of antiplatelet therapy and the type of
CVD. Patients with a history of prior myocardial infarction were more likely to be
on antiplatelet therapy (86%) than those with a history of peripheral vascular disease
(77%) or cerebrovascular accident (CVA) (69%). Furthermore, only 54% of patients with
CVA and no other CVD were using an antiplatelet agent. Antiplatelet therapy has been
shown to reduce the risk of recurrent CVA by 11% to 15% in patients with prior ischemic
stroke of non-cardiac origin and reduce the risk of stroke, MI, and vascular death,
by 22% [28]. The extent to which stroke patients and their physicians avoid antiplatelet therapy
due to risk of bleeding is not known. This lower use of antiplatelet therapy in stroke
patients identifies an area for potential investigation and intervention to improve
anti-platelet regimens in this patient population.

Health insurance coverage has been shown to be an important factor in the delivery
of medical services. Increasing levels of health insurance have a positive correlation
with the likelihood that an individual will receive appropriate preventive care [29]. In diabetes, poor insurance coverage has been associated with delayed or omitted
preventive services [30]. We found that health insurance coverage was not an important predictor of anti-platelet
therapy in patients of this cohort, but the level of health insurance coverage was
high and subjects were under the care of a primary care provider suggesting good access
to care. In the case of an expensive medicine like clopidogrel, lack of prescription
drug coverage could contribute to lack of use. However, aspirin, which comprises the
majority of the antiplatelet agents in our study, is a low cost, nonprescription medication.

This study has several limitations. Our population, while representative of patients
receiving primary care in the rural Northeast may not be representative of all adults
with diabetes in the U.S. We do not have information regarding allergies or side effects
associated with antiplatelet medications. It is possible that eligible subjects were
unable to tolerate therapy, though it is unlikely this would be the case in more than
5% of subjects. It is unlikely that medication intolerance would be correlated with
age, sex or cardiovascular disease. We do not have information regarding the indication
for aspirin use, though 98% of subjects reported low-dose aspirin use (< = 325 mg/d)
suggesting prophylaxis. Our analysis does not indicate causality and the exact mechanisms
promoting or deterring the use of recommended interventions is unknown.

There have been a variety of successful interventions directed at increasing the use
of antiplatelet therapy for the prevention of CVD including: HMO-directed quality
improvement efforts [31], intensive multifaceted case management [32], pharmacy-directed interventions [33,34], and electronic medical record reminder systems [35]. A VA study found that physician counseling was highly associated with antiplatelet
therapy and suggested that this simple intervention could prevent many cardiovascular
events and deaths [36]. There are many ways in which antiplatelet use can be increased; it is now a question
of which approach can be most efficiently adapted in each clinical setting.

Conclusion

Despite clinical practice guidelines recommending antiplatelet therapy for patients
with diabetes, there are still many eligible patients not receiving this beneficial
therapy, particularly patients under 65, women, and patients without known CVD. Effective
methods to increase antiplatelet use should be considered at the national, community,
practice and provider level.

Acknowledgements

Funded by the National Institute of Diabetes and Digestive and Kidney Diseases (R01
DK61167 and K24 DK068380).